Benzocarbazolones



United States Patent 3,329,686 BENZOCARBAZOLONES Stephen Sallay,Wynnewood, Pa., assignor to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Filed Mar. 23, 1964,Ser. No. 354,149 9 Claims. (Cl. 260-315) This invention relates tobenzocarbazolones and more particularly to substitutedhexahydrobenzocarbazol-S-ones and to the method by which these newcompounds are prepared.

The new compounds of this invention include those encompassed within thefollowing structure:

wherein R and R are selected from the group consisting of hydrogen,lower'alkyl and lower alkoxy and R and R taken together are O-CH O-; Ris selected from the group consisting of hydrogen, lower alkyl and loweralkoxy; R is selected from the group consisting of hydrogen, lower alkyland benzyl and X is selected from the group consisting of =0 and =NNH Asused herein, loweralkyl is intended to include straight or branchedhydrocarbons having 5 or less carbon atoms.

The new compounds of the present invention are prepared according to thefollowing reaction sequence which while directed to the preparation of asingle compound encompassed within those defined by Formula I representsthe reaction by which other compounds falling within the class definedby Formula I are prepared.

N-NH: N-N- H H To prepare the new compounds of the present invention, ahexahydro-l,4-naphthoquinone II is reacted with phenylhydrazine III byrefluxing the reactants in the presence of an inert solvent for a periodof from about minutes to about 2 hours. The resulting intermediate IV, anaphtho- 'quinone-l-phenylhydrazone, is then cyclized as shown to yieldthe desired product V, a benzo(a) carbazol-S-one.

The starting materials shown are known to those skilled in the art orare prepared by known methods. This is particularly so with thephenylhydrazine III and substituted derivatives of the same. Thestarting 1,4-naphthoquinone derivative rep-resented by II, the latterbeing specifically 2,3,4a,5,8,8a-hexahydro-1,4-naphthoquinone areprepared according to the method of O. Diels and K. Alder, Ber.,

3,329,686 Patented July 4, 1967 "ice 62, 2337, 1929. It is of courseunderstood that the starting naphthoquinone II will be suitablysubstituted as by R (see Formula I) to provide the final product IV withsuch a substituent. As shown in Formula I, R is present in the startingnaphthoquinone at the 8 (or 5, depending on nomenclature) position whichis equivalent to the 4 position of the final product I. The Rsubstituents which may be present on starting compound II, when R isother than hydrogen, are those previously defined with respect toFormula I and more specifically identified hereinafter.

The phenylhydrazine (III) reacted with the starting naphthoquinone II iswell known in the art. The phenyl hydrazine is substituted at the 3 and4 positions when R and R are other than hydrogen, to provide the finalproduct with the R and R substituents, as specified, at the 8 and 9positions of the final product I.

In order to obtain the final products encompassed within Formula I,wherein R represents a substituent other than hydrogen, it is necessaryto further react a compound of the type shown at V, i.e. wherein thereis a hydrogen atom at the 11 position, with a suitable reagent. Such areaction is carried out with the compound V, or derivatives thereof withsodium hydride or sodium amide in a selected, inert solvent such asdimethylformamide, toluene or the like followed by reaction with alkylhalide or a halide derivative, such as a benzyl halide including thesubstitutedderivatives thereof.

Having obtained the final products represented by V, in the reactionsequence shown, further reaction of such a product (V) with hydrazinehydrate results in the product represented by VI. It will be noted thatthe latter represent those compounds wherein the X substituent ofFormula I is This reaction is carried out by suspending the benzo(a)carbazol-S-one (V) in an inert solvent and refluxing the reactionmixture for a period of from 10 minutes to about 1 hour. On cooling thedesired product crystallizes out and is recovered in a conventionalmanner, yielding the desired hydrazone VI.

The new compounds of the present invention encompassed within thosedefined by Formula I have valuable properties which make them useful forpharmacological purposes. More specifically, the new compounds of thepresent invention are useful as blood pressure reducing or depressingagents.

When used as blood pressure depressants, the new compounds of thisinvention may be administered alone or in combination withpharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmaceutical practice. They maybe administered orally in the form of tablets or capsules containingsuch excipients as starch and milk surgar. They may be administered inthe form of lozenges in which the active ingredient is mixed with sugar,corn syrups, flavoring agents and dyes. They may be administered orallyin the form of solutions which may contain coloring and flavoringagents. They may also be injected parenterally.

The dosage of the present therapeutic agents which will be most suitablewill vary with the form of administration and the particular compoundchosen, and will also vary with the particular patient under treatment.Treatment will be started with small dosages substantially less than theoptimum dose of the compound and increase the dosage by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the agent will be required to produce the sameeffect as a smaller quantity given parenterally. The compounds areuseful in the same manner as other agents having a similar function andthe dosage level is of the same order of magnitude as is generallyemployed with these other therapeutic agents. The therapeutic dosage maybe from 10 to 500 milligrams per day and may be administered in severaldifierent dosage units. Tablets containing from 25 to 250 mg. of activeagent are particularly useful.

These new compounds (X=O) are also useful in the preparation of the newcompounds disclosed in my copending application Serial No. 354,092,filed Mar. 23, 1964, relating to 5-aminobenzocarbazoles, now US. PatentNo. 3,274,188, issued Sept. 20, 1966.

Reference now to the specific examples which follow will provide abetter understanding of the new compounds of the present invention asWell as the novel method by which these new compounds are prepared.

Example I 2,3,4a,5,8,8a-hexahydro-1,4-naphthoquinone (II) (0. Diels andK. Alder, Ber., 62, 2337, 1929) (16.4 g.) is covered With 200 ml. ofmethanol and refluxed with 10.0 g. of phenylhydrazine for twentyminutes. After cooling, crystals separate out, M.P. 164-166 C. The crudeproduct, 2,3,4a,5,8,8a-hexahydro-1,4-naphthoquinone l-phenylhydrazone(1V), is recrystallized from ethanol; M.P. 170-172 C. IR spectrumexhibited absorption at 5.85 (x0).

l-phenylhydrazone derivative IV (52.0 g.) is dissolved in 470 ml. ofacetic acid which is previously saturated with dry hydrochloric acid atroom temperature. The temperature of the red colored reaction mixturerises up to 55 C. within two-three minutes and ammonium chlorideseparation begins. After fifteen minutes the reaction mixture is cooledand poured onto alkaline ice Water. A white crystalline precipitateseparates out, 36.0 g. (82% The crude material recrystallized frommethanol alfords shiny needles, 1,4,4a,5,6,11b -hexahydro-11H-benzo(a)carbazol-S-one (V), M.P. 192193 C. IR spectrum possesses the expectedbonds at 2.90 (NH), and 5.84 (0x0). U.V spectrum had the indole maximaat 224, 280, and 291 m Example II Following the procedure of Example I,-methyl-2,3, 4a,5,8,8a-hexahydro-1,4-naphthoquinone is reacted with3,4-dimethylphenylhydrazine with the resulting product being cyclizedwith acid to yield 4,8,9-trimethyl-1,4,4a, 5,6,1 lb-hexahydro-l lH-benzo(a) carbazole-S-one.

Example III According to the procedure of Example I, S-methoxy-2,3,4a,5,8,8a-hexahydro 1,4 naphthoquinone is reacted withp-methoxyphenylhydrazine with the resulting product being acidified toyield 4,8-dimethoxy-1,4,4a,5,6,11bhexahydro-1 lH-benzo (a)carbazol-S-one.

Example IV Following the procedure of previous examples,5-propyl-2,3,4a,5,8,8a-hexahydro-1,4-naphthoquinone is reacted with3,4-dimethoxy-phenylhydrazine and the resulting product acidified toyield 8,9-dimethoxy-4-propyl-1,4,4a,5,6,1lb-hexahydro-l1H-benzo(a)carbazol-S-one.

Example V According to the method of Example I, 5-ethoxy-2,3,4a,5,8,8a-hexahydro-1,4-naphthoquinone is reacted with3,4-methylene-dioxyphenylhydrazine and the resulting intermediateproduct cyclized with dilute acid to produce 8,9methylenedioxy-4-ethoxy-1,4,4a,5,6,1lb-hexahydrol1H-benzo( a)carbazole-S-one.

Example VI Reacting 5 methyl 2,3,4a,5,8,8a-hexahydro-1,4-naphthoquinonewith p-butyl-phenylhydrazine results in an intermediate product which onbeing cyclized yields 8-butyl- 4 methyl 1,4,4a,5,6,11bhexahydro-11H-benzo(a)carbazol-S-one.

4;- Example VII According to the method previously described, 4-ethyl-1,4,4a,5,6,1 lb-hexahydro-l 1H-benzo( a) carbazol-5-one is obtained byreacting 5-ethyl-2,3,4a,5,8,8a-hexahydro-1,4- naphthoquinone withphenylhydrazine and cyclizing the resulting product by acid treating.

Example VIII Following the procedure previously described, reacting5-ethyl-2,3,4a,5,8,Sa-hexahydro-1,4-naphthoquinone with 3 ethyl 4methylphenylhydrazine produces a product which on acid treatment yields4,9-diethyl-8-methyl-1,4,4a,5,6,11b-hexahydro-11H-benzo(a)carbazol-S-one.

Example IX Reacting the product of Example I with sodium hydride indimethylformamide followed by reaction with ethyl chloride results in11-ethyl-1,4,4a,5 ,6,11b-hexahy-dro-1 1H- benzo (a) carbazol-S-one.

Example X Reacting the product of Example I with benzylbromide accordingto the method described in Example IX results in 11benzyl-1,4,4a,5,6,1lb-hexahydro-l1H-benzo(a)carbazol-S-one.

Example XI Reacting the product of Example I with butylbromide accordingto the method of Example IX results in 11- butyl 1,4,4a,5,6,11bhexahydro 11H benzo(a)carbazol-S-one.

Example XII Reacting the product of Example II with benzyl-bromideaccording to the method of Example IX, there is obtained 11-benzyl-4,8,9-trimethyl-1,4,4a,5,6,1lb-hexahydro-l1H-benz0(a)carbazol-S-one.

Example XIII Reacting the product of Example III with propylchlorideaccording to the method of Example IX, one obtains 4,8 dimethoxy 11propyl 1,4,4a,5,6,11b hexahydro- 11H-benz0(a) carbazol-S-one.

Example XIV Reacting the product of Example IV with benzylbromideaccording to the method of Example IX, there is produced 11 benzyl 8,9dimethoxy 4 propyl 1,4, 4a,5 ,6, 1 lb-hexahydro-l lH-benzo (a)carbazol-S-one.

Example XV Reacting the product of Example VII with benzylbromideaccording to the method of Example IX, one obtains1l-benzyl-4-ethyl-1,4,4a,5,6,1l b-hexahydro-llH- benzo(a)carbazol-5-0ne.

Example XVI To obtain 11-benzyl-8,9-:dimethoxy-4-ethyl-1,4,4a,5,6,llb-hexahydro-l1H-benzo(a)carbazol-S-one, one reacts benzylbromide with8,9-dimethoxy-4-ethyl-1,4,4a,5,6,11bhexahydro-11H-benzo(a)carbazol-S-one according to the method of previous examples.

Example XVII Example XIX Reacting the product of Example XVIII withbenzylbromide according to the method of Example IX, there is produced4-ethyl-11-benzyl-1,4,4a,5,6,1lb-hexahydro- 11H-benzo(a) carbazol-S-one.

Example XX According to the method of Example XX, 4-ethy1-11- benzyl1,4,4a,5,6,11b hexahydro 11H benzo(a) carbazol-S-one, hydrazone isprepared by reacting 4-ethy1- 11 benzyl 1,4,4a,5,6,11b hexahydro 11Hbenzo(a) carbazol-S-one with hydrazine hydrate.

Example XXIII To prepare 4-methyl-8,9-dimethoxy-11-benzyl-l,4,4a,5,6,11b hexahydro 11H benzo(a)ca.rbazol 5 one, hydrazone, 4 methyl 8,9dimethoxy 11 benzyl 1,4, 4a,5,6,11-b hexahydro 11H benzo(a)carbazol 5one is reacted with hydrazine hydrate according to the method of ExampleXX.

Example XXIV To prepare 11-benzyl=1,4,4a,5,6,1lb-hexahydro-IIH- benzo(a)carbazol-S-one, hydrazone, 11-benzyl-1,4,4a,5,6,11'b-hexahydro-11H-benzo(a)carbazol-5-one is reacted with hydrazinehydrate according to the method of Example XX.

Example XXV Following the method of Example XX, 8,9-dimethyl-4- ethyll,4,4a,5,6,11b hexahydro 11H benzo(a)carbazol-S-one is reacted withhydrazine hydrate to prepare 8,9 dimethyl 4 ethyl 1,4,4a,5,6,11bhexahydro- 1 lH-benzo (a) carbazol-S-one, hydrazone.

Example XXVI Following the method of previous examples, 4,8,11-trimethyl1,4,4a,5,6,11b hexahydro 11H benz-o(a)carbazol-S-one is reacted withhydrazine hydrate to prepare 4,8,11 trimethyl 1,4,4a,5,6,11b hexahydro11H- benzo(a) car-bazol-S-one, hydrazone.

6 Example XX VII According to the method of previous examples, hydrazinehydrate is refluxed with 11-benzyl-8-propyl-1,4,4a,5,6,1lb-hexahydro-l1H-benzo(a)carbazol-S-one to produce 11 benzyl 8 propyl1,4,4a,5,6,1lb hexahydro 11H- benzo (a) carbazol-S-one, hydrazone.

While the present invention has been described with some degree ofparticularity, it is to be understood that such description is notintended in any manner to be construed as a limitation on the scope ofinvention. The invention is to be limited only by the claims appendedhereto.

The invention claimed is:

1. A compound having the formula:

wherein R and R are selected from the group consisting of hydrogen,lower alkyl and lower alkoxy and R and R taken together are OCH -O-; Ris selected from the group consisting of hydrogen, lower alkyl and loweralkoxy; R is selected from the group consisting of hydrogen, lower alkyland benzyl; and X is selected from the group consisting of :0 and =N-NH2. 1,4,4a,5,6,11-b hexahydro 11H benzo(a)carbazol-5-one.

3. 11 lower alkyl 1,4,4-a,5,6,11b hexahydro 11H- benzo(a)carbazol-S-one.

4. 11 ethyl 1,4,4a,5,6,11b hexahydro 11H benzo- (a)carbaz0l-5-one.

5. 11 benzyl l,4,4a,5,6,11b hexahydro 11H- benzo(a)carbazol-5-one.

6. 4 ethyl 11 benzyl 1,4,4a,5,6,11b hexahydro- 1 IH-benzo (a)car-bazol-S-one.

7. 4,8 dimethoxy 1,4,4a,5,6,1lb hexahydro 11H- benzo a) carbazol-S-one.

8. 1,4,4a,5,6,11b hexahydro 11H benzo(a)carbazol-S-one, hydrazone.

9. 4 ethyl 11 benzyl 1,4,4a,5,6,11b hexahydro- 1 lH-benzo (a)carbazol-S-one, hydrazone.

References Cited UNITED STATES PATENTS H 3,215,691 11/1965 Freed et a1.260-315 OTHER REFERENCES Mann et al., J. Chem. 500., pp. 1525-9 (1958).

WALTER A. MODANCE, Primary Examiner.

I. M. FORD, Assistant Examiner.

1. A COMPOUND HAVING THE FORMULA: